Department of Signal Transduction

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Research Group

ProfessorNobuyuki Takakura
Assistant ProfessorHiroyasu Kidoya
Assistant ProfessorHisamichi Naito

Research Projects

It is well known that the development of normal tissues and organs requires the generation of tissue-specific cells from stem cells. The maintenance of this stem cell system also requires the generation of an appropriate microenvironment. Blood vessels are the most essential structures in tissues and organs, as without blood vessel formation, almost all tissues cannot develop (there are some exceptions). In our research group, we are analyzing the molecular mechanisms by which blood vessels form in physiological and pathological conditions, including in cancers and inflammation. We are also elucidating the mechanisms that cause stem cells to associate closely with blood vessels. Ultimately, we wish to employ our results to establish strategies that will inhibit the malignant progression of various diseases.

Our specific research projects are as follows:

I. Analysis of the molecular mechanism of blood vessel formation
　1) Molecular analysis of angiogenesis, with a particular focus on the Tie1 and Tie2 receptors.
　2) Physiologic and pathologic function of endothelial stem cells (ESCs).
　3) Molecular characterization of arterio-venous patterning, with a particular focus on the apelin/APJ system. 　

II. Molecular analysis of self-renewal in normal and cancer stem cells
　1) Analysis of cell cycle regulation in stem cells, with a special focus on Galectin-3 and the GINS complex.
　2)Establishment of a strategy that can inhibit the formation of the vascular niche inhabited by cancer stem cells.

Fig.1
Figure 1. Maturation of blood vessels.
We elicited the concept that Angiopoietin-1 (Ang1) from mural cells (MCs) generates structurally stable blood vessels by inducing cell adhesion between endothelial cells (ECs) and MCs (Takakura, Immunity 1998). In addition, we found that Ang1 from hematopoietic stem cells (HSCs) induces non-leaky new blood vessels during angiogenesis (Takakura, Cell 2000, Yamada, J Exp Med 2006). Apelin produced from ECs on stimulation with Ang1 induces non-leaky and enlarged blood vessels (Kidoya, EMBO J 2008, Blood 2000). Apelin overexpression induces larger blood vessels in tumors and promotes effective drug delivery into tumors (Kidoya, Oncogene 2012), thereby suppressing tumor growth.


Fig.2
Figure 2. Endothelial stem cells (ESCs) and angiogenesis.
During angiogenesis, the tip cells in front of new vessels determine the migration direction of the new vessels, stalk cells produce a higher number of endothelial cells (ECs) for elongation, and finally phalanx cells induce the maturation of new blood vessels. We recently identified ESCs in the preexisting blood vessels that may generate heterogeneous ECs as described above, and that play a critical regulatory role in pathological and physiological angiogenesis (Naito, EMBO J 2012).


Fig.3
Figure 3. Vascular niche of cancer stem cells.
By using PSF1, a component of the DNA replication factor GINS, we succeeded in identifying cancer stem cells (CSCs) in the vascular niche (Nagahama, Cancer Res 2010, Matsui, Am J pathol 2013). Moreover, we found that stromal CD44 acts as a niche factor that supports the stemness of CSCs
(Kinugasa, Stem Cells 2014).


Major publications

  1. Kinugasa Y, Matsui T, Takakura N. CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells. 2014 Jan;32(1):145-56.
  2. Muramatsu F, Kidoya H, Naito H, Sakimoto S, Takakura N. microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Oncogene. 2013 Jan 24;32(4):414-21.
  3. Sakimoto S, Kidoya H, Naito H, Kamei M, Sakaguchi H, Goda N, Fukamizu A, Nishida K, Takakura N. A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice. Development. 2012 Apr;139(7):1327-35.
  4. Naito H, Kidoya H, Sakimoto S, Wakabayashi T, Takakura N. Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J. 2012 Feb 15;31(4):842-55.
  5. Kidoya H, Kunii N, Naito H, Muramatsu F, Okamoto Y, Nakayama T, Takakura N. The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene. 2012 Jul 5;31(27):3254-64.

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